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Prodrug: Approach to Better Drug Delivery

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 International Journal of Pharmaceutical Research
2012, Volume 4, Issue 1, 15-21.
ISSN 0975-2366

Research Article
Prodrug: Approach to Better Drug Delivery

Vikram Lohar,* Sandeep Singhal, Vimal Arora.

Faculty of Pharamaceutical Science, Jodhpur National University, Jodhpur (Raj.) India
*Corresponding author: Email lohar.vikram@gmail.com singhalsandeep87@yahoo.in Ph no.: 07737596989
Received:15/02/2011, Revised: 15/03/2011, 25/03/2011
ABSTRACT
Prodrugs as pharmacologically inactive chemical derivatives that could be used to alter the physiochemical properties of
drug in a temporary manner or to increase their usefulness and to decrease associated toxicity. A prodrug is compound
formed by chemical modification of biologically active compound that will liberate the active compound in vivo by enzymatic
or chemical processes. In both drug discovery and drug development, prodrugs have become an established tool for
improving physicochemical, biopharmaceutical or pharmacokinetic properties of pharmacologically active agents that
overcome barriers to a drug's usefulness. To illustrate the applicability of the prodrug strategy, this article describes the most
common functional groups that are amenable to prodrug design, and highlights examples of prodrugs that are either
launched or are undergoing human trials, strategies explored to date for site selective drug delivery, including CNS, Liver,
Kidney targeted drug delivery, Antibody based targeting, targeting the viruses, Anti HIV targeting, Colon targeting drug
delivery and novel approaches eg. prodrug incorporated delivery system including liposome, lipoprotein, emulsion and
solid lipid nanoparticles.

KEY WORD: Prodrug, Novel approaches, BBB, Colon targeted drug delivery

INTRODUCTION It should be inactive or less active than parent

Many therapeutic drugs have undesirable properties
that may become pharmacological, pharmaceutical, or
pharmacokinetic barriers in clinical drug application.
Among the various approaches to minimize the
undesirable drug properties while retaining the desirable
therapeutic activity, the chemical approach using drug
derivatization offers perhaps the highest flexibility and
has been demonstrated as an important means of
improving drug efficacy. The prodrug approach, a
chemical approach using reversible derivatives, can be
useful in the optimization of the clinical application of a
drug. In 1958, Albert initially coined the term prodrug and
used it to a pharmacologically inactive compound that is
transformed by the mammalian system into an active
substance by either chemical or metabolic means [1]. This
included both compounds that are designed to undergo a
transformation to yield an active substance and those that
were discovered by serendipity to do so. These two
situations were distinguished by Harper, who in 1959
introduced the term drug latentiation to refer to drugs that
were specifically designed to require bioactivation [2]. The
type of prodrug to be produced depends on the specific
aspect of drug's action that requires improvement and the
type of functionality that is present in the active drug [3].
What is Prodrug? Albert et al. described Prodrugs as
pharmacologically inactive chemical derivatives that could
be used to alter the physiochemical properties of drug in a
temporary manner or to increase their usefulness and to
decrease associated toxicity. A prodrug is compound
formed by chemical modification of biologically active
compound that will librate the active compound in vivo by
enzymatic or chemical processes. They have also been
called latentiated drugs, bioreversible derivatives and
biolabile drug-carrier conjugates [4-13]
Ideal requirements of Prodrugs: An ideal prodrug must
meet the following requirements:
compound. The linkage between drugs and carrier must be
cleaved in vivo. The carrier molecule released in vivo must
be nontoxic. The metabolic fragment of carrier molecule
apart from drug should be nontoxic. It should not have
intrinsic pharmacological activity that means it should not
change receptor configuration that is necessary for
pharmacological response [14].
Characteristics of Prodrugs
It can be identified by the covalent linkage
between the drug molecule and the promoiety (carrier
group).Prodrug is less active or inactive form of the
drug.The prodrug must be readily transported to site of
action. It is a biologically reversible modified form of the
parent drug.The promoiety after the release of the drug
must not show any toxic effects, also should not produce
its pharmacological action [15].
CLASSIFICATION OF PRODRUGS
A.Depending upon the constitution,lipophilicity, method
of bioactivation and catalyst involved in bioactivation:
Prodrugs are classified into two categories: 1. Carrier-
Linked Prodrugs: Contains an active drug linked with a
transport moiety (promoeity) which is mostly lipophilic in
nature and is removed enzymatically. Depending on carrier
used these may further be classified into: Bipartate - These
prodrugs comprised of one carrier attached to the
active substance or the drug.Tripartate - In these prodrugs,
the active drug is linked to the carrier moiety through a
spacer or connector group.Mutual - It cosist of two
pharmacologically active, usually synergistic agents
coupled together to form a single molecule such that each
acts as the carrier for the other.e.g. Benorylate is a
mutual prodrug of NSAIDs aspirin and paracetamol. 2.
Bioprecursors: or metabolic precursors (prodrug) are
obtained by chemical modification of active drug but
not contain a caarier. Such type of prodrug has almost the
IJPR | January-March | 15
 Lohar et al / International Journal of Pharmaceutical Research 4(1) 15-21

same lipophilicity as the parent drug is bioactivated extracellular body fluids (e.g., etoposide phosphate,
generally by redox biotransformation. e.g. Amine getting valganciclovir, fosamprenavir) [22]
oxidized to COOH, to afford the active drugs [16, 17].
DESIGN AND DEVELOPMENT OF PRODRUG
Table 1: Barriers to Drug Usefulness and Corresponding Many successes have been recorded in prodrug design and a
Objectives of Prodrug Design. large variety of such compounds have proven their
Barriers To Drug Objectives Of Prodrug therapeutic value. Prodrug design aims at overcoming a
Usefulness Design number of barriers to a drug's usefulness. The major
Pharmaceutical barriers Pharmaceutical objectives of prodrug design derive from these
Insufficient chemical objectives considerations and are also listed in Table 1. Several
stability, Poor solubility Improved formulation complementory view adderessing prodrugs namely:-a.their
offensive taste or (e.g., increased chemical classification: (i) Carrier linked prodrugs (ii)
Odor, Irritation or pain hydrosolubility) Bioprecursors b. their mechanism of activation: (i)
Improved chemical Enzymatically (ii) Non enzymatically c.their tissue
stability selectivity:(i) Brain targeting (ii) Liver targeting (iii) Kidney
Improved patient targeting (iv) Tumor targeting (v) Antibody based targeting
acceptance and (vi) Targeting the virus (vii) Colon targeting delivery the
compliance possible production of toxic metabolites [21].
Pharmacokinetic Pharmacokinetic
barriers objectives FUNCTIONAL GROUP CONSIDERATIONS FOR
Low oral absorption, Improved bioavailability, PRODRUG DERIVATIZATION AND REACTIONS
Marked presystemic Prolonged duration of Prodrug structures for the most common
metabolism, Short duration action functionalities, such as carboxylic, hydroxyl, amine,
of action Improved organ selectivity phosphate/phosphonate and carbonyl groups, include esters,
Unfavourable distribution carbonates, carbamates, amides, phosphates and oximes.
in the body However, various other, more uncommon, functional
Pharmacodynamic Pharmacodynamic groups have been investigated as potentially useful
barriers objectives structures in prodrug design. Thiols, for example, react in a
Toxicity Decreased side effects similar manner as alcohols and can be derivatized to
thioethers and thioesters. Amines may be derivatized into
B. Chemical classification imines bases. Some typical prodrug structures for the most
Chemiclly Prodrugs can be categorized into following common functionalities are given in Fig. II
classes: a) Ester prodrug: By suitable esterification of
molecules containing a carboxylic Acid or hydroxyl group, Reactions involve during prodrug design
it is possible to attain derivatives with almost any desirable So many biological factors may affect enzymatic
hydrophilicity, lipophilicity, and in vivo liability. Examples reactions that the resulting interspecies and inter
of ester prodrugs include bacampicillin, pivampicillin, individual variability renders prodrug design
pivmecillinam and cefuroxime axetil Prednicarbate, unreliable and sometimes even problematic. To
candesartan cilexetil etc. b) Amines prodrug: Derivatization circumvent such difficulties, increasing number of studies
of amines to give amide has not been widely Used as a have proposed and investigated prodrugs activated by a
prodrug because of high chemical stability of amide and purely or predominantly non-enzymatic mechanism.
lack of amidase enzyme necessary for hydrolysis. A more Prodrug of this type includes: (2-oxo-1,3-dioxol-4-yl)methyl
common approach is to use Mannich base as a prodrug esters Mannich bases oxazolidines esters with a basic side
form of amines. Example: Hetacillin c) Azo prodrugs: chain sterically able to catalyze intramolecular hydrolysis
Amines are derivatized to azo linkage prodrug esters and amides undergoing intramolecular nucleophilic
occasionally.Example: sulphasalazine Carbonyl prodrugs: cyclization-elimination. Phosphorylation lipidization
Carbonyl functionalities such as aldehydes and ketones esterification pegylations [22-24].
conversion to prodrug have not found wide clinical
utility. Example:-Hexamine release formaldehyde in the Difficulties in prodrug design
urine (acidic pH), which act as an antibacterial agent [3, 14, Minimize the no. of purposed candidates. Maximize
18-19]. the explored space of physio chemical or
pharmacokineticproperties. Minimize the additional
C. New classification: Many therapeutic agents are synthetic work reach target physio chemical profile.Reach
manufactured and administered in prodrug forms. A new urgent pharmacokinetic profile.Reach target metabolic
classification system for prodrugs is proposed to provide behaivior in particular target rate of activation [23].
useful information about where in the body a prodrug is
converted to the active drug. In this system, prodrugs are Limititions of prodrug design
classified into Type I or Type II and the respective Even if mutual prodrug design has proven highly
Subtypes IA, IB, IIA, IIB or IIC based on their sites of beneficial in overcoming various undesiarable
conversion into the final active drug form. For Type I properties of drugs, it can also give to a large number
prodrugs, conversion occurs intracellularly (e.g., antiviral of newer difficulties especially in assessment of
nucleoside analogs, lipid-lowering statins), whereas pharmacological, pharmacokinetics, toxicological and
conversion of Type II prodrugs occurs extracellularly, for clinical properties.One of biggest problem that can arise in
examples in digestive fluids, systemic circulation or other prodrug design is the toxicity which may be due to-
Formation of unexpected metabolites from total prodrug

16 | IJPR | January-March
 Lohar et al / International Journal of Pharmaceutical Research 4(1) 15-21
that may be toxic. The inert carrier generated following
cleavage of prodrug may also transform into a toxic
metabolite. During its activation stage the prodrug might
consume a vital cell constituent such as glutathione leading
to its depletion [23].
Table 2: Prodrug with Improved Taste
PRODRUG WITH IMPROVED
PARENT DRUG
TASTE
CHLORAMPHENICOL PALMITATE ESTER
CINDAMYCIN PALMITATE ESTER
SULFISOXAZOLE ACETYL ESTER
TRIAMCINOLONE DIACETATE ESTER
PRODRUG INCORPORATED DELIVERY SYSTEM
(NOVEL APPROACHES)
The colloidal drug delivery system works as a
controlled and sustained delivery by releasing the
encapsulated drug while in circulation or after the
recognition by cell, so it is necessary that the delivery
system must contain maximum quantity of drug for
optimum efficacy. The encapsulation depends upon the
physicochemical properties which can suitably modified by
linking with promoiety and altering as prodrug.
Liposome
Liposomes are consisting of lipid (mainly
phospholipids) bilayer in which between lipid bilayer
intervening water molecules are present. The drug is
incorporated into either aqueous compartment or in the
lipid bilayer as the drug has its physicochemical
property. The less hydrophobic drug exhibit low
entrapment efficiency and making them more hydrophobic
by derivative of fatty acids , improves the entrapment
efficiency of delivery system e.g. the triamcinolone 21
palmitate (prodrug) showed 85% entrapment efficiency
as compared to triamcinolone acetonite which has 5%
entrapment efficiency .
Liporotein
Lipoprotein are endogenous transporter of lipids in the
circulation, they are non immunogenic escapes recognition
by reticulo endothelial system. Their structural components
are NeoHDL particles consisting of apolar triglyceride
core surrounded by phospholipids monolayer in which
specific apoprotein are imbedded. Since apoprotein are
necessary for the recognition of Low Density Lipoprotein
so drug should be into the lipid moiety but most of the
drug has not sufficient lipophilic so there is need of to
prepare lipophilic prodrug.
Emulsion
The oil in water emulsion are used as sustained
drug delivery, by passing targeted to macrophages and
active targeting by ligand attachment, so in this case the
lipophlicity of the drug is necessary to make as oil in
water emulsion as sustained delivery system. e.g.
Esterified phenolic 4 hydroxy derivative of etoposide is
used as lipophilic prodrug which is soluble in lipid
emulsion in which cholesteryl ester oil used as oil
component.
Solid Lipid Nanoparticle
Solid lipid nanoparticle consisted of high melting
point triglyceride as the solid core and a phospholipids
coating. Its advantage over the other system is use of
natural lipid and incorporation of drug in triglyceride core
which may be applicable for prolonged release. For
prolonged release it is desirable to incorporate the drug
into triglyceride phase of emulsion. e.g. Azidothymidine
palmitate ester prodrug incorporation increases as
compared to Azidothymidine [25-26].
Table 3: Prodrugs to Reduce Gastric Irritation.
Parent drug
Prodrugs That Cause No
Gastric Distress
Salicylic acid Salsalate, Aspirin
Diethyl stilbestrol Fosfestrol
Kanamycin Kanamycin pamoate
Phenylbutazone N-methyl piperazine salt
Nicotinic acid Nicotinic acid hudrazide
Oleandrin Oleandrin acetate
APPLICATIONS
Pharmaceutical applications Improvement of taste
Two approaches can be utilized to be overcome the
bad taste of drug. First is reduction of drug solubility in
saliva and the other is to lower the affinity of drug towards
taste receptors, thus making the bitterness or causticity
imperceptible.17 Examples of drugs with improved taste are
given in Table 2.
Improvement of odour
The odor of drug depends on its vapor pressure; a
liquid with high pressure will have a strong odor. Ethyl
mercaptan is one such drug which is a foul smelling liquid
of B.p 35. It is, useful in the treatment of leprosy, is
converted into its phthalate ester, diethyldithio-
isophthlate which has higher b.p and is less odorless. The
prodrug is administered by rubbing on skin. After
absorbtion, the ester is metabolized to parent drug by
thioesterases [17].
Reduction in GIT Irritation
Despite the intensive research that has been aimed at the
development of NSAIDs, their clinical usefulness is still
restricted by their GI side effects like gastric irritation,
ulceration, bleeding, and perforation and in some cases
may develop into life threatening conditions. Glycine
methyl ester conjugate of ketoprofen, and histidine methyl
ester conjugate of diclofenac, and various conjugates of
flurbiprofen with amino acid like L-tryptophan, L-histidine,
phenylalanine and alanine as mutual prodrugs were
reported to have less ulcerogenicity with better anti-
inflammatory/analgesic action than their parent drugs.
Emaxples of produgs designed to overcome such
problems of gastric distress are given in Table 3 [27-32].
Improved Chemical Stability
A drug may destabilize either during its shelf life or in
the GIT when used orally shelf-life stability is particularly
important in case of drugs for intravenous use. The prodrug
design of such agents is also a good alternative to improve
stability. An example of this is the anti neoplastic drug,
azacytidine. The solution of this drug is readily hydrolyzed
but the bisulfate prodrug is stable to such a degradation at
IJPR | January-March | 17
 Lohar et al / International Journal of Pharmaceutical Research 4(1) 15-21
acidic pH and is more water soluble than the parent drug.
The prodrug converts to active drug at the physiological pH
of 7.4 [17].
Improve Patient Acceptance and Compliance
One of the reasons for poor patient compliance,
particularly in case of children, is the bitterness, acidity
or causticity of drug. Two approaches can be utilized to
overcome the bad taste of drug: 1) Reduction of drug
solubility in saliva. 2) Lower the affinity of drug towards
taste receptors. e.g: Clindamycin has bitter taste, so it is not
well accepted by children. It was found that by increasing
the chain length of 2-acylesters of clindamycin, the taste
improved from bitter to non bitter taste (Phosphate ester)
[14].
Improved Aqueous Solubility
Many of the water soluble prodrugs for enhanced
oral drug delivery include the addition of an ionizable
progroup to the parent compound (such as phosphate
group), Oral phosphate prodrugs are cleaved at the
intestinal brush border by membrane bound alkaline
phosphatase just prior to the passive absorption of the
active drug through the intestinal membrane, thus providing
a great concentrational driving force for absorption in the
intestinal lumen. The challenges to the development of oral
phosphate prodrug, are related to poor enzymatic
bioconversion (usually the aqueous solubility of the
phosphate prodrug is enhanced to such an extent that
passive diffusion through the intestinal membrane is
prevented), the precipitation of the parent drug after
enzymatic cleavage in the intestinal lumen and poor
permeability of the parent drug. Estramustine phosphate is
a phosphate ester prodrug of estramustine (Emcyt),
which was launched in the mid 1970s for the treatment of
prostate carcinoma and is marketed in both injectable
and oral formulations. After the dephosphorylation of
the water soluble estramustine phosphate to
estramustine, it is metabolized to its ketone derivative,
estromustine. Further metabolism of estramustine and
estromustine produces two active metabolites,
estradiol and estrone. Thus estramustine phosphate has
a dual mechanism of action, i.e. the estramustine and
estromustine exert cytotoxic (antimicrotubule) effects
and estradiol and estrone are responsible for
antigonadotropic activity. After oral administration,
estramustine phosphate is rapidly converted to
estramustine in the GItract, and approximately 75 % of
the drug is absorbed. The bioconversion of intravenously
administered estramustine phosphate to estramustine is
slower with the halflife of 1.3 hours in plasma [22, 33].
2) Pharmacokinetic Applications
Improved lipophilicity
Prodrugs are most frequently applied to mask polar
and ionizable groups of a drug molecule with the aim to
improve the membrane permeability and oral absorption.
Oseltamivir (Tamiflu) is an orally active prodrug of
oseltamivir carboxylate, a selective inhibitor of viral
neuramidase glycoprotein of influenza A and B and it
has been proposed to have antiviral activity also against
avian H5N1 virus, the virus responsible for the bird flu. As
an ethyl ester, oseltamivir is rapidly and well absorbed from
the GItract and it increases the oral bioavailability of
oseltamivir carboxylate from 5% to 79%. Oseltamivir
18 | IJPR | January-March
undergoes rapid bioconversion to oseltamivir carboxylate
mostly by human carboxylesterase 1 and the maximum
plasma concentration of oseltamivir carboxylate is
reached within 3 to 4 hours after oral administration of
oseltamivir (elimination half life = 610 hours) [22, 34].
Prodrugs for prolonged duration of drug action
Although various pharmaceutical formulations are
frequently used to prolong the duration of drug action, there
are a few examples where prodrugs have been used for this
purpose. Very lipophilic prodrugs of several steroids (e.g.
testosterone nandrolone) and neuroleptics (e.g.
fluphenazine, flupenthixol, and haloperidol) are
slowly released from the site of intramuscular injection
and result in a prolonged duration of action. Once released
from the injection site, the prodrugs are usually rapidly
bioconverted, in most cases with no attenuation of their
therapeutic action. As an example, the onset of action of
fluphenazine generally appears between 24 to 72 hours
after injection of its lipophilic decanoate ester prodrug,
and thus gradual release continues for 1 to 8 weeks with an
average duration of 3 to 4 weeks [14, 22].
Carrier mediated absorption
Prodrugs targeted towards specific membrane
transporters are designed to have structural features that
mimic the natural substrates of the endogenous uptake
transporters present on the intestinal epithelium. Targeting
specific transporters is particularly important for drugs
that are either so polar or so charged that they have
negligible passive absorption. Peptide transporters appear to
be attractive targets in prodrug design, as they are widely
distributed throughout the small intestine and show
sufficiently high transport capacity and broad substrate
specificity. Valacyclovir (Valtrex) is a representative
example of a prodrug that exploits carrier mediated
transport. Valacyclovir is an oral L-valine amino acid ester
prodrug of acyclovir, an antiviral agent used against herpes
zoster virus. Valacyclovir is a substrate of human intestinal
peptide transporter (hPEPT1), and it is rapidly
transported across the intestinal membranes.
Bioconversion of valacyclovir to acyclovir by valacyclovir
hydrolase (VACVase) is efficient as over 99 % of
valacyclovir is converted to acyclovir. The bioavailability
of acyclovir after oral administration of valacyclovir is
enhanced from 20 % to 54 % with the tmax of a 2 hours [22].
Prodrugs for improve intravenous administration
While examples of marketed water soluble oral
prodrugs are rare, there are several successful prodrugs with
improved solubility properties for i.v. administration.
The most commonly used approach to increase the water
solubility by prodrugs is to introduce an ionizable/polar
promoiety into the parent drug. A number of phosphate
esters have been developed as potential water soluble
prodrugs for i.v. administration and less commonly for
oral administration Fosphenytoin (Cerebyx) is a
phosphate ester prodrug of poorly water soluble phenytoin
for the acute treatment of seizures, and can be used for
either i.v. or intramuscular administration.22 Fluconazole is
a broad-spectrum antifungal agent that is active by both oral
and intravenous administration for the treatment of
superficial and systemic infections. However, the IV
formulation available is a 2 mg/mL dilute solution in
saline for infusion. The prodrug fosfluconazole was
 Lohar et al / International Journal of Pharmaceutical Research 4(1) 15-21
developed to increase the solubility of the parent drug for
production of a low volume parenteral formulation, which
would allow access to bolus administration as well as higher
IV doses. Fosfluconazole is a unique example of a
phosphate prodrug in that it results from direct
phosphorylation of a tertiary alcohol [34].
Prodrugs for improved topical administration
Topical administration of drugs encompasses all
external membranes, though ocular and dermal drug
delivery are the most widely used forms of topical prodrug
applications. The unfavourable physicochemical properties
of many drug molecules lead to poor permeation across the
stratum corneum of the skin or the corneal barrier of the
intraocular tissues. These features can often be achieved by
the prodrug approach. A prostaglandin analog latanoprost
(Xalatan) represents a new class of active ocular
hypotensive agent for the treatment of glaucoma. It is a
lipophilic isopropyl ester prodrug that is rapidly
hydrolyzed inside the ocular tissue to biologically active
prostaglandins. In its carboxylic acid form, the active drug
is poorly permeable and causes irritation while the
lipophilic prodrug achieves improved ocular absorption and
better safety [19, 34].
Prodrugs for site selective drug delivery
Site selective drug delivery is the ultimate goal in
drug therapy. Site selectivity may be achieved by passive
drug enrichment in the organ, via transporter mediated
delivery, by selective metabolic activation through
enzymes, and by antigen targeting. E.g. CNS, tumor and
liver targeting are discussed in more detail below.
CNS targeted drug delivery
Going to extremes on the lipophilic precursor scale, a
possible choice for CNS prodrugs is coupling the drug to a
lipid moiety, such as fatty acid, glyceride or
phospholipids. Such prodrug approaches were explored
for a variety of acid-containing drugs, like levodopa,
GABA, Niflumic acid, valproate or vigabatrin are coupled
to diglycerides or modified diglycerides. While increased
lipophilicity may improve movement across the BBB, it
also tends to increase uptake into other tissues, causing an
increased tissue burden [36] Levodopa (Dopar) can be
considered as a prodrug which achieves targeted delivery
into central dopaminergic neurones. Levodopa is a
substrate for the neutral amino acid transporter (LAT1)
expressed at the BBB. This uptake transporter carries
levodopa to the brain tissue, where levopoda is rapidly
converted to dopamine by enzymes only present in
nerves. After the bioconversion, a very hydrophilic
dopamine is trapped into the CNS, enabling its
pharmacodynamic effects selectively in brain tissue.
Levodopa is usually administered along with peripheral
dopa decarboxylase inhibitors (DCI), such as carbidopa or
benserazide. Thus the peripheral decarboxylation to
dopamine, norepinephrine, and epinephrine by dopa
decarboxylase can be avoided leading to diminished risk of
undesired cardiovascular and gastrointestinal side effects
[22].
Colon targeting
The polar prodrug decreasing the absorption in the
stomach and intestine while selective cleavage by bacterial
enzyme present in colon to more lipophilic drug follows fast
absorption through the membrane of colon, thus targeting to
colon is achieved, e.g. sulphasalazine which is formed by
coupling of diazotized sulphanilamide pyridine with 5-
amino salicylic acid (ASA). On oral administration intact
sulphasalazine reaches the colon. The azo reductase
associated with colonic microflora convert
sulphasalazine to its constituent's entities, the active
species 5-amino salicylic acid (ASA) available for
absorption in colon, while precolonic absorption
responsible for side effects is reduced [25]. As described
above, an ideal prodrug approach for colonic delivery is
to develop a prodrug that is transported intact through
the stomach and small intestine but is hydrolyzed to release
an active drug by action of enzymes produced by bacterial
microflora of the colon [34-35].
Liver targeted drug delivery
Since the liver is the most important metabolizing
organ, it possesses a wide variety of liver specific
metabolizing enzymes capable of prodrug activation.
Pradefovir mesylate is acyclic 1, 3 propanyl ester prodrug of
a nucleoside monophosphate (NMP), adefovir, which is
being tested for the use in the treatment of hepatitis B.
Pradefovir undergoes a cytochrome P450 (CYP) 3A4
catalyzed oxidation predominantly in liver hepatocytes. The
oxidation results in ring opening and elimination of an aryl
vinyl ketone. The released monophosphate adefovir is further
converted by nucleotide kinases to the active nucleoside
triphosphate (NTP). In phase II clinical trials in hepatitis B
patients, pradefovir has demonstrated good efficacy with
low systemic adefovir levels, which is indirect evidence for
liver targeting [22].
Kidney targeting
For the treatment of renal hypertension Dopamine is
used because of binding to specific receptor present in the
kidney but its therapeutic index is small as it precipitates
high blood pressure by interaction with the -adrenergic
receptor. This can be overcome by the advantage of
fact that their glutamil derivative of amino acid and
peptides selectively accumulate in the kidney. Such
derivative on reaching kidneys is acted upon by two
enzymes that present in high concentration in the renal
tissue, glutamyl transpeptidase and L-aromatic amino
acid decarboxylase to release active drug. The release of
dopamine levels produces marked increases in renal blood
Antibody based targeting
Prodrugs can be designed to target specific enzymes
or carriers by considering enzyme substrate specificity or
carrier-substrate specificity in order to overcome various
undesirable drug properties. This type of "targeted-prodrug"
design requires considerable knowledge of particular
enzymes or carrier systems, including their
molecular and functional characteristics. Recently,
advances in gene cloning and controlled gene expression
techniques in mammalian cells allow the elucidation of the
molecular nature of enzymes and carrier proteins and
make possible more rational design of "targeted-prodrugs.
Monoclonal antibody is ideal way of targeting tumor cells.
Two approaches are used for targeting and activating a
prodrug at the tumor site. These are called antibody drug
conjugate and antibody directed enzyme prodrug therapy
(ADEPT) [6].
IJPR | January-March | 19
 Lohar et al / International Journal of Pharmaceutical Research 4(1) 15-21
Antibody drug immunoconjugate formed by linking
cytotoxic agent to monoclonal antibodies active with
tumor associated antigen. The immunoconjugate bind
to specific cells leading to internalization of conjugate
and drug is cleaved from the antibody intracellularly
(lysosomal degradation).The limiting factor for this
approach is heterogeneity in expression of antigen by cancer
cells, insufficient internalization of the antigen antibody
complex or inefficient cleavage of linker moiety to
release the free drug.
The second approach involves administration of
enzyme that is covalently linked to a monoclonal
antibody, which bind selectively to the respective
tumor associated antigen. After the antibody enzyme
conjugate has localized within the tumor and has cleaved
from non target sites, a prodrug that is substrate
for the enzyme is administered, when prodrug
contact with enzyme, it is converted to active drug
species at the tumor site.25, 26, 38 Capecitabine (Xeloda) is
an orally administered carbamate prodrug of 5-fluoro
Uracil, equiring a cascade of three enzymes for its
bioconversion to the active drug. Capecitabine is
absorbed intact from the intestine and undergoes the
final step of the bioconversion pathway within the
tumors, thus avoiding systemic toxicity. The enzymatic
bioconversion pathway is initiated in the liver, where
human carboxyl esterases 1 and 2 cleave the ester bond of
the carbamate This is followed by a rapid, spontaneous
decarboxylation reaction resulting in the formation of
5'deoxy 5-fluorocytidine (5'dFCyd). The reaction continues
in the liver, and to some extent in tumors, by cytidine
deaminase which converts 5'dFCyd to 49 5'deoxyuridine
(5'dFUrd). The final activation step takes place in the
tumors; wherein thymidine phosphorylase (dThdPase)
liberates the active drug 5- fluorouracil. The bioavailability
of 5-fluorouracil after oral administration of capecitabine is
almost 100 % and the safety profile of capecitabine is much
more favorable compared to that of intravenous 5-
fluorouracil.
Targeting the Viruses
The antiviral drug Acyclovir has been targeted through
site selective activation by the herpes virus encoded
enzyme pyrimidine deoxynucleoside (thymidine) kinase,
responsible for converting acyclovir to its monoester
form. Again monoester converted into triester by cellular
kinase. The triester is pharmacologically active form. The
enzymatic conversion of triester form is found in the
herpes infected cells, so Acyclovir shows high
therapeutic activity against herpes virus and low activity
against uninfected host cells. The HIV protease inhibitor
amprenavir was approved by the FDA in 1999 for use
in adults and children with HIV infection, but its limited
water solubility requires the use of softgel formulation for
delivery and multiple pills for a single dose. Dan Todd of
GlaxoSmithKline presented fosamprenavir calcium as a
prodrug of amprenavir with improved aqueous
solubility. After screening 60 prodrugs in vitro and in vivo
assays, the phosphate prodrug, fosamprenavir calcium
(GW-433908), was selected for its high water solubility,
solution and solid-state stability, and rapid conversion to
the parent drug on the apical side of epithelium. The
prodrug is delivered from a solid dosage form with a
lower pill burden, two tablets replacing eight amprenavir
softgels. Fosamprenavir calcium was approved by the FDA
20 | IJPR | January-March
in October 2003 for use in combination with other
antiretroviral agents for the treatment of HIV infection in
adult [25-26, 39-40].
3) Pharmacodynamic Application
Decreased side effect
Prodrugs can be used to afford drugs that would be too
toxic to be given directly, a feature of the slow release.
Propanaldehyde is useful for aversion therapy in
patients addicted to alcohol. However, it is a highly
irritating chemical and causes allergic reactions. As an
alternative, a closely related compound, pargyline is used.
The prodrug that is converted to the active drug at the
target site itself greatly reduced side effects of highly toxic
drugs [15].
To improve membrane transport
Barbiturates are a group of compounds responsible for
profound sedative and hypnotic effect. They are weakly
acidic in nature and converted to the corresponding sodium
salt in aqueous sodium hydroxide. The sodium salt is
extensively employed for i.v anaestic properties.
Barbituric acid is the parent member of this group of
compounds. Hexobarbitone was found to be effective drug
but its membrane permeability was found to be low.
However N-methyl hexobarbitone a simple derivative of the
parent drug was found to have better permeability [14].
CONCLUSION
Prodrug have become an established concept and a
powerful tool in optimizing overcoming physiochemical,
pharmaceutical and biopharmaceutical barriers to a drugs
usefulness thus prodrugs can be used to help in enhancing
poor water solubility, permeability or chemical stability, to
prolong the duration of action, to improving drug
targeting, reduction in GIT irritation, reduction in toxic
side effect. There are many approaches for prodrug delivery
like prodrug in liposomes, in neosomes, in lipoprotein, in
emulsion, in solid lipid nanoparticle, linking of drug to
lipoprotein, micelle forming polymeric prodrug.
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